8G9P

Tricomplex of RMC-4998, KRAS G12C, and CypA

8G9P の概要

• エントリーDOI: 10.2210/pdb8g9p/pdb
• 分子名称: GTPase KRas, Peptidyl-prolyl cis-trans isomerase A, PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, small gtpase, cancer, tricomplex, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 78191.45

構造登録者

Tomlinson, A.C.A.,Saldajeno-Concar, M.,Knox, J.E.,Yano, J.K. (登録日: 2023-02-21, 公開日: 2023-08-16, 最終更新日: 2024-10-16)

主引用文献

Schulze, C.J.,Seamon, K.J.,Zhao, Y.,Yang, Y.C.,Cregg, J.,Kim, D.,Tomlinson, A.,Choy, T.J.,Wang, Z.,Sang, B.,Pourfarjam, Y.,Lucas, J.,Cuevas-Navarro, A.,Ayala-Santos, C.,Vides, A.,Li, C.,Marquez, A.,Zhong, M.,Vemulapalli, V.,Weller, C.,Gould, A.,Whalen, D.M.,Salvador, A.,Milin, A.,Saldajeno-Concar, M.,Dinglasan, N.,Chen, A.,Evans, J.,Knox, J.E.,Koltun, E.S.,Singh, M.,Nichols, R.,Wildes, D.,Gill, A.L.,Smith, J.A.M.,Lito, P.
Chemical remodeling of a cellular chaperone to target the active state of mutant KRAS.
Science, 381:794-799, 2023

PubMed Abstract: The discovery of small-molecule inhibitors requires suitable binding pockets on protein surfaces. Proteins that lack this feature are considered undruggable and require innovative strategies for therapeutic targeting. is the most frequently activated oncogene in cancer, and the active state of mutant KRAS is such a recalcitrant target. We designed a natural product-inspired small molecule that remodels the surface of cyclophilin A (CYPA) to create a neomorphic interface with high affinity and selectivity for the active state of KRAS (in which glycine-12 is mutated to cysteine). The resulting CYPA:drug:KRAS tricomplex inactivated oncogenic signaling and led to tumor regressions in multiple human cancer models. This inhibitory strategy can be used to target additional KRAS mutants and other undruggable cancer drivers. Tricomplex inhibitors that selectively target active KRAS or multiple RAS mutants are in clinical trials now (NCT05462717 and NCT05379985).

PubMed: 37590355
DOI: 10.1126/science.adg9652

実験手法

X-RAY DIFFRACTION (1.5 Å)